The present invention relates to the field of pharmacological compositions and methods of utilizing such compositions in order to improve air flow throughout the upper respiratory system. More specifically, the present invention discloses compositions having powerful surfactant effect upon the air/liquid interface resident upon the epithelial lining of the upper respiratory systemxe2x80x94and the use of such compoundsxe2x80x94in order to open air spaces and air ways which have become partially or completely obstructed by proximal epithelial wall collapse and/or adhesion caused by the presence and effect of highly viscous mucous exudatexe2x80x94generated as a product of inflammatory responsexe2x80x94secreted thereupon.
Pathological conditions can arise from, and can cause changes in surface tension values of air/liquid interfaces resident upon tissue surfaces, especially epithelial surface tissues, of and within various organs of mammalian anatomy. The naturally occurring xe2x80x9csurfactant systemxe2x80x9d secreted upon the epithelial lining of the lung which is deficient in cases of R.D.S. is known to be comprised of a complex mixture of lipids, proteins and carbohydrates (as described in a recent review: Surfactants and the Lining of the Lung, The John Hopkinds University Press, Baltimore, 1988).
The prime function of the surfactant system is to stabilize the alveoli and associated small airways against collapse by decreasing the surface tension at the air/liquid interface. It is now believed that the action of the phospholipid component of the surfactant system is the principal source of the powerful surface tension reduction effect of the naturally occurring surfactant system of the lung. More specifically, it is known that the fully saturated diacylphospholipids, principally dipalmitoyl phosphatidylcholine (DPPC), provide liquid balance and anti-collapse properties to the lung""s epithelial lining. In addition to DPPC, spreading agents, also found within the naturally occurring surfactant system, assist DPPC in rapidly forming a uniform spread film on the air/liquid surfaces of the lung. Such spreading agents include cholesteryl esters such as, for example, cholesteryl palmitate (CP); phospholipids such as, for example, diacylophosphatidylglycerols (PG), diacylphosphatidylethanolamines (PE), diacylphosphatidylserines (PS), diacylphosphatidylinositols (PI), sphingomelin (Sph) and Cardiolipin (Card) and virtually and other phospholipid, and the lysophospholipids; or any of the plasmalogens, dialklylphospholipids, phosphonolipids; carbohydrates and proteins, such as, for example, albumin, pulmonary surfactant proteins A, B, C and D. The naturally occurring surfactant system is further described in U.S. Pat. No. 5,306,483.
DPPC has been administered to infants with respiratory distress syndrome as a therapeutic measure in order to restore deficient or low levels of natural surfactant. For this purpose, DPPC has been administered by means of an aqueous aerosol generator (utilized with an incubator in which the infant resided during treatment). Endotracheal administration has also been utilized. DPPC therapy has been typified as utilizing natural surfactants (harvested from porcine or bovine lungs), or artificial, commercially synthesized compounds.
It has also heretofore been disclosed to utilize therapeutic agents, in combination with surfactant/spreading agents to effectively administer drug therapy uniformly throughout the epithelial lining of the lung. U.S. Pat. No. 5,306,483 (the xe2x80x9c""483 patentxe2x80x9d) discloses a process to prepare lipid crystalline figures in fluorocarbon propellants for the delivery of therapeutically active substances which form amorphous fluids on delivery at the air/liquid interface of the lung and which can be utilized as an effective drug delivery system. More specifically, said patent discloses a process comprising (a) preparing a mixture of one or more lipids of the group of phospholipids known as phosphatidylcholines and one or more spreading agents, in powder form and a therapeutically active substance and one or more fluorocarbon propellants, said lipids, spreading agents and therapeutically active substances being insoluble in the propellants; and (b) evaporating the propellants from the mixture. The ""483 patent teaches the combination of dipalmitoyl phosphatidylcholine (DPPC) or any of the other fully saturated Acyl chain phospholipids, 80.0 to 99.5% by weight, and other spreading agents, for example, phospholipids such as, but not limited to PG, PE, PS, PI, lysophospholipids, plasmalogens, dialkylphospholipids, diether phosphonolipids, Cardiolipin, sphingomyelin, 0.5 to 20.0% weight; neutral lipids like cholesteryl esters such as, but no limited to, cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate, 0.5 to 10% by weight, carbohydrates, such as, but not limited to, glucose, fructose, galactose, pneumogalactan, dextrose, 0.5 to 10% by weight; and proteins such as, but not limited to albumin, pulmonary surfactant specific proteins A, B, C, and D 0.5 to 10% by weight, yielding lipid-crystalline structures in fluorocarbon (both chloro- and hydrofluorocarbon) propellants in which therapeutically active agents, drugs and other materials can be carried into the lungs after release from and through metered dose nebulizer. The spreading agents referred to in the ""483 patent are compounds such as the above-described phospholipids, lysophospholipids, plasmalogens, dialklyphospholipids, phosphonolipids, carbohydrates and proteins. The function of the spreading agent is to assist DPPC, or other phospholipids such as, for example, DPPG, in rapidly adsorbing and forming a spread film upon the air/liquid surfaces of the lungs. In addition, the ""483 patent also discloses a process for preparing such lipid crystalline figures in fluorocarbon propellants without a therapeutically active substance for use as a tear (as for the eye).
The mammalian upper respiratory system is comprised of various conduits and chambers especially adapted for conduction of air to and away from the lungs. Besides forming a simple conduit, the upper respiratory system is responsible for warming, moisturizing, and removal, by means of entrapment and filtration, the various impurities found in inspired air so as to protect the lower respiratory system from disease and irritation, while simultaneously conditioning inspired air for maximum gas exchange. Generally, the upper respiratory system can be said to be comprised of the nose, nasal cavity, nasopharynx, paranasal sinuses, oropharynx and laryngopharynx.
As ambient air is inspired through the nose, it first passes through the external nares where relatively large hairs filter and remove larger particles from the air stream. From the external nares, the air is then drawn through the nasal cavity for further filtration. Within the nasal cavity, small boney protuberances known as the nasal conchae line the lateral walls of the chamber. The conchae, also known as turbinate bones, create great turbulence within the inspired air. The conchae thereby increase the collision and contact of smaller particulate matter with the adherent mucous coating of the epithelial surfaces lining the nasal cavity. Thus, such particles that avoid filtration by nasal hairs may become trapped within the nasal cavity. Mucous producing goblet cells which create the mucous coating of the upper respiratory system, assisted by the movement of cilia located on the free border of the epithelial cells, acts to continually flush such particulate matter, and any organisms which they may carry, towards the pharynx where they are swallowed and any such organisms destroyed in the acidic environment of the stomach. In addition, mucous production may also flush such matter out of the system through the external nares.
The paranasal sinuses also act as a filtration system in that the mucous membranes lining the sinuses also tend to trap impurities entering these structures during inspiration. Likewise, the nasopharynx, lined with respiratory epithelium, is also covered with mucoid secretions and capable of trapping and eliminating particulate contaminants in a similar manner.
As stated above, the upper respiratory system provides a conduit for the passage of air to the lungs. During normal physiologic function, the filtering structures and activities of the upper respiratory system do not interfere or present increased resistance to inspiration. However, during times of increased inflammatory activity, localized edema, or swelling of nasal and sinus membranes, can cause great resistance to normal respiration.
As discussed in greater detail below, inspired antigenic material can induce, through the inflammatory response, a marked increase in goblet cell mucous production. In addition, the inflammatory response quite often results in increased permeability of capillaries located close to the epithelial lining. Such increased permeability results in a localized edema or swelling of the epithelial lining of the upper respiratory system as various components of blood seep into the interstitial spaces. More specifically, such increased permeability allows the entry of white cells into the epithelial tissue where they may complex with the antigenic trigger of the inflammatory reaction resulting in phagocytosis, lysis, and enzymatic destruction of such foreign material. The localized edemaxe2x80x94observed as substantial swelling of the epithelial lining of the upper respiratory systemxe2x80x94tends to narrow the airways and airspaces. In addition, another common inflammatory response to antigenic challenge is the increased production of mucous and secretion of same upon the epithelial lining. The proteinaceous remnants of inflammatory phagocytosis, lysis and enzymatic destruction, discussed above, combines with the increased quantity of mucous to form an unusually viscous mucous coating upon the epithelial lining exhibiting higher levels of surface tension.
During the course of upper respiratory inflammationxe2x80x94characterized by the aforementioned edema and copious viscous mucousxe2x80x94opposing mucous laden epithelial surfaces lining the nasal cavity and sinusesxe2x80x94that ordinarily provide the above-described filtering functionsxe2x80x94may become so swollen as to contact one another and so reduce airway volume. In addition, such swelling may be great enough, in the case of sections of the airway and airspaces demonstrating diminutive diameter, to allow proximal and/or opposing epithelial surfaces to come into direct continuous or intermittent contact. Upon such contact, the viscous mucoid exudate resident upon such surfaces may cause, due to the high surface tension properties discussed above, partial or complete closure of such air ways and air spaces.
For example, during the course of a common cold, bout of influenza, bacterial infection or allergy attack, antigenic proteins of such viruses, bacteria, and/or antigenic particles (for example, pollens, dust, dust mites, or other particulate antigenic material) present in inspired air may become trapped upon the normally present mucous coating of the lining epithelium whereupon the come into contact with macrophages. Such macrophages may induce an initial immune response by presenting such antigenic material to T-lymphocytes such as, for example, a CD4+ T lymphocyte. Upon such presentation, CD4+ lymphocytes respond, in part, by releasing a multitude of interleukins and cytokines which, in turn, promote the production of IgE. Mast cells, in close proximity with capillaries of the upper respiratory mucosa are induced by action of such IgE to secrete histamine. At the same time, histamine production increases both the volume of blood entering the tissue from local capillaries as well as increasing goblet cell production of mucous. In addition, presentation of antigen to lymphocyte leads to a cascade of inflammatory activity wherein pmns, with activated antibody, leach out of capillaries which have been made permeable thereto by histamine, into the respiratory epithelium wherein they complex with antigen for phagcytotic, lytic and macrophagic activities. The release of arachidonic acid from such activated mast cells, macrophages and pmns may lead to, for example, the production of luekotrienes. Luekotrienes, have inflammatory effects similar to histamine. However, luekotrienes effect such chemotaxis and enhanced mucous production to a far greater degree than histamine.
As discussed above, histamine and luekotrienes both act to vastly increase capillary permeability which, in turn, results in a general swelling of the mucosa as additional anti-body laden white blood cells leach out of said capillaries to form antibody-antigen complexes. Phagocytosis of such complexes by pmns, macrophages, and/or annihilation by means of the complement destruction cascade produces much waste material. This highly proteinaceous material, when added to the increased mucous secretions induced by these inflammatory pathways, forms copious amounts of viscous mucous resident upon said epithelial lining exhibiting substantially greater surface tension than that generated by the air/liquid interface of the epithelial lining in the absence of inflammation.
Two inflammatory effects, localized edema and increased exudate surface tension act, in concert, to promote and enable the above-described attraction and adhesion of proximal epithelial surfaces to one another leading to increased air way and air space resistance. However, it is the high surface tension properties of the mucoid secretions that allow and promote proximal inflamed tissues to remain adherent upon each other. In the absence of such increased surface tension, edema alone would, in many instances, only result in intermittent contact of proximal surfaces of the epithelial lining.
It has been heretofore possible to treat the underlying immune response with drugs effective in decreasing or eliminating same. For example, reduction of the production of mucous secretions is well known through the use of both anti-histamines and antiluekotreines. Indeed, such drug therapy may be effective in opening portions of the upper respiratory system closed by the combination of edema and increased mucous production discussed above. However, the use of anti-histamines may have undesired side effects such as, for example, drowsiness as they are often systemic in effect. Certain medications effective at reducing mucous production and inflammation such as, for example, pseudoephedrine, may cause nervousness, dry mouth, and other effects. Generally, undesirable side effects of such antihistamine type medications are dose dependent with greater dosagexe2x80x94required in some instances to effectively reduce viscous mucous production, and decrease edemaxe2x80x94leading to an increase in such side and adverse effects. In addition, although mucous production may be annoying and uncomfortable, increased production of mucous and increased activity of the muco-ciliary transport system during the course of an upper respiratory infection serves the important function of flushing out bacteria while simultaneously preventing infection spread to the lung. Therefore, a drastic decrease or elimination of mucous production during the course of upper respiratory inflammatory episodes is not necessarily a desirable mode of treatment.
What is needed is a composition and method of delivering same which is effective in lowering the surface tension of the increased viscous mucous produced during inflammation of the upper respiratory system without effecting the purging effect of the muco-ciliary system, but rather assisting said system in washing out by products of the inflammatory process from the upper respiratory system while promoting the opening of the air spaces and air ways within.
Although the above-described medications may have undesirable side effects, such effects, systemic in nature, may be reduced by application of reduced amounts of such agents directly to the effected the upper respiratory epithelium. Thus, such therapeutics, administered via nasal inhalation, may be utilized to place the maximum amount of agent on the target tissue while minimizing systemic exposure. However, it has heretofore not been possible to ensure that such medication, delivered via nasal inhalation, was delivered uniformly upon the epithelial surfaces of the upper respiratory system. What has been needed is a therapeutic agent carrier capable of providing direct and uniform application of such agents directly to such target tissue.
It is known that an analogous increase in surface tension occurs during episodes of otitis media. Otitis media is a pathological condition common to mammalian species, and most common to children. During episodes of otitis media, fluid accumulates in the middle ear or, as it is also known, the tympanic cavity.
Although, as described below, surfactant compositions, both natural and artificial, have been heretofore known, formulated and utilized to decrease surface tension within the lung, no such compositions, or methods for administering said compositions, have been heretofore suggested, taught or disclosed in regards to decreasing the surface tension within the lumen of the eustachian tube. Likewise, no method has heretofore been known which provides an effective decrease in opening resistance of the eustachian tube while simultaneously enhancing the pressure equilibration functions thereof.
Additionally, although such surfactant compositions have been known, formulated and utilized to decrease surface tension within the lungs, no such compositions, or methods of administering said compositions, have been heretofore suggested, taught or disclosed in regards to decreasing the surface tension of the epithelial mucosa lining the upper respiratory system so as to decrease the resistance to air flow therethrough or to utilize such methods and compositions to provide an improved and highly effective means of delivering therapeutic agents effective in the treatment of upper respiratory disorders, such as for example, bacterial infections, viral infections and allergies which may all result in the above-described swelling, increased surface tension, and reduction of air flow resulting from an inflammatory response thereto.
U.S. patent application Ser. No. 09/450,884, the entire disclosure of which is hereby incorporated by reference, discloses a composition and method especially formulated and adapted to increase and enhance mammalian eustachian tube lumen patency and pressure equalization performance by dramatically decreasing the surface tension of the lumenal surface of the eustachian tube. In the method and composition disclosed therein, a mixture of one or more lipids and one or more spreading agents selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form, and one or more fluorocarbon propellants is prepared. The lipids and the spreading agents are advantageously selected to be insoluble in the propellants. The lipids utilized in practicing said method are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of about 0.5 to about 20 percent by weight, both based upon the total weight of the mixture. Combination of the one or more lipids, one or more spreading agents and one or more fluorocarbon propellants results in the formation of lipid crystals and described in more detail, below. A metered dose of the mixture of lipid crystals is then administered, via an external nasal orifice into a mammal upon which the present method is practiced.
Upon administration, the propellant(s) are evaporated from the mixture and the lipid crystals are deposited at a nasopharyngeal, or as it may also be described, an anterior terminus, of a subject mammalian eustachian tube whereupon said lipid crystals come into contact with lumen surfaces of the tube. Upon contact with lumen surface tissue and air/liquid interfaces of the eustachian tube lumen, the mixture of lipid crystals forms an amorphous spread film upon said air/liquid interface effectively decreasing the opening pressure thereof.
The lipid crystals deposited upon the lumen surfaces and air/liquid interface thereupon is comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity. In addition, the spreading agent combined therewith provides complete and uniform distribution of the surfactant over and upon the lumen air/liquid surface resulting in substantial decreases in lumen opening pressure. In turn, the decrease in lumen opening pressure results in greater patency of the eustachian tube and thereby providing a resultant increase in fluid conduction/equalizing function of this anatomical structure.
Administration of the aerosolized lipid crystals through the nasal orifice also results in deposition of said crystals upon the mucosal surfaces of the sinus passages and sinus airways. The mucosal surfaces of these airways and sinuses also demonstrates an air/liquid interface formed by the secretion of muco and muco-serous secretions thereupon. Upon deposition of the lipid crystals upon these mucosal surfaces, said crystals form a uniform and amorphous spread film and effectively reduce the surface tension thereupon. Therefore, said method and composition also contemplates reduction of the surface tension of the air/liquid surfaces resident upon mammalian sinus and sinus air way mucosal surfaces.
In a second preferred embodiment of the invention disclosed in U.S. patent application Ser. No. 09/450,884, a method of administering therapeutically active agents, effective in the treatment of otitis media, directly to mammalian eustachian tube and middle ear target tissues is disclosed. In the method of the second embodiment of said invention, a mixture of one or more lipids, one or more spreading agents, one or more therapeutically active agent(s), effective in the treatment of otitis media, and one or more fluorocarbon propellants is prepared. The one or more lipids and spreading agents are advantageously selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates, and proteins, all being in powder form. The one or more lipids, spreading agents and therapeutically active agent(s), effective in the treatment of otitis media, are also advantageously selected to be insoluble in the propellants. In practicing the method of the second embodiment of the invention disclosed therein, the lipids are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of about 0.5 to about 20 percent by weight, both based upon the total weight of said mixture. The mixture resulting from the combination of lipid(s) spreading agent(s) and therapeutically active agent and propellant forms lipid crystals which act as carriers for said therapeutically active agent. A metered dose of the mixture of lipid crystals is then administered, via an external nasal orifice, into a mammal upon which the method is practiced. A suitable bottle equipped with a metered dose valve and nasal administration adaptor is advantageously utilized for this purpose.
Upon administration of the lipid crystal mixture, the propellants, carry the lipid crystals in combination with therapeutically active agent(s) effective in the treatment of otitis media to the nasopharyngeal terminus of the eustachian tube whereupon the propellant(s) evaporate. The lipid crystals and therapeutically active agent is then deposited upon the tissues of the eustachian tube including the epithelial lined lumen whereupon the mixture forms an amorphous spread film effectively carrying said therapeutically active agent effective in the treatment of otitis media uniformly through the eustachian tube and to target tissues of the middle ear. Therefore, said composition and method are disclosed and provides for the administration of therapeutically active agents directly to lumen surfaces of mammalian eustachian tubes, and also, by means of said eustachian tube lumen, to middle ear target tissues wherein said therapeutically active agents provide effective treatment for otitis media while, in addition, providing the same increased eustachian tube patency and performance as the first embodiment.
Although the above-described therapeutic agents useful in treating the disorders causative of upper respiratory inflammation may have undesirable side effects, such effects, systemic in nature, may be reduced by application of reduced amounts of such agents directly to the effected tissues of the upper respiratory system. Thus, such therapeutics, administered via nasal inhalation, may be utilized to place the maximum amount of agent on the target tissue while minimizing systemic exposure. However, it has heretofore not been possible to ensure that such medication, delivered via oral or nasal inhalation, was delivered and distributed uniformly upon the epithelial surfaces of the upper respiratory system or delivered with a carrier capable of significantly reducing the above-described increased surface tension without the use of additional drugs. What is needed is a compound and method wherein a carrier is provided capable of providing direct and uniform application of therapeutically active agents effective in the treatment of upper respiratory inflammation, as well as the disorders causative thereof, directly to epithelial lining of the upper respiratory system, while, independently of said agents, providing a decrease in upper respiratory air flow resistance therethrough by means of powerful surfactant effect.
Now, in accordance with the present invention, a method of increasing and enhancing air flow through the mammalian upper respiratory system is disclosed wherein high surface tension resulting from viscous mucous resident upon the epithelial lining of upper respiratory air ways and air spaces is substantially reduced so as to promote the opening of said air ways and air spaces for facilitation of respiration therethrough.
In the first preferred embodiment of the present invention, a mixture of one or more lipids and one or more spreading agents selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates and proteins, all in powder form, and one or more fluorocarbon propellants is prepared. The lipids and spreading agents are advantageously selected to be insoluble in the propellants. The lipids utilized in practicing the method of the present invention are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of about 0.5 to about 20 percent by weight, both based upon the total weight of the mixture. Combination of the one or more lipids, or one or more spreading agents and one or more fluorocarbon propellants results in the formation of lipid crystals and described in more detail, below. A metered dose of the mixture of lipid crystals is then administered, via nasal or oral inhalation, into the upper respiratory system of a mammal upon which the present method is practiced.
Upon administration, the propellant(s) are evaporated from the mixture and the lipid crystals are deposited upon the air/liquid interface resident upon the epithelial lining of the air ways and air spaces of the upper respiratory system whereupon said lipid crystals form an amorphous spread film thereupon so as to effectively decrease the surface tension thereof, open and increase the volume thereof so as to decrease resistance to air flow therethrough.
The lipid crystals deposited upon the epithelial surfaces lining the upper respiratory system and air/liquid interface thereupon is comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity. In addition, the spreading agent combined therewith provide complete and uniform distribution of the surfactant over and upon the air/liquid surface resident upon said lining. In turn, the decrease in surface tension afforded thereby tends to separate proximal epithelial lining adherent, one upon the other, so as to increase air way and air space volume and to decrease air flow resistance. In addition, said decrease in surface tension also minimizes and, in some instances, eliminates the collection of fluids therewithin which might otherwise also serve to occlude, or partially occlude said air ways and air spaces. Administration of the aerosolized lipid crystals through nasal or oral inhalation results in deposition of said crystals upon the mucosal surfaces of entire upper respiratory system including the sinus passages and sinus airways.
In a second preferred embodiment of the present invention, a method of administering therapeutically active agents effective in the treatment of upper respiratory congestion and inflammation as well as those agents effective in the treatment of disorders causative thereofxe2x80x94directly to the upper respiratory epithelial liningxe2x80x94is disclosed. In the method of the second embodiment of the present invention, a mixture of one or more lipids, one or more spreading agents, one or more therapeutically active agent(s), effective in the treatment of upper respiratory airway inflammation, and/or the underlying cause thereof and one or more fluorocarbon propellants is prepared. The one or more lipid and spreading agents are advantageously selected from the group consisting of cholesteryl esters, phospholipids, carbohydrates and proteins, all being in powder form. The one or more lipids spreading agents and therapeutically active agent(s), effective in the treatment of said airway restriction, are also advantageously selected to be insoluble in the propellants. In practicing the method of the second embodiment of the present invention, the lipids are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of 0.5 to 20 percent by weight, both based upon the total weight of said mixture. The mixture resulting from the combination of lipid(s) and spreading agent(s) and therapeutically active agents and propellant forms lipid crystals which act as carriers for said therapeutically active agents. A metered dose of the mixture of lipid crystals is then administered via nasal or oral inhalation, into the upper respiratory system of a mammal upon which the method is practiced. A suitable bottle equipped with a metered dose valve and nasal or oral administration adaptor is advantageously utilized for this purpose.
Upon administration of the lipid crystal mixture, the propellants, carry the lipid crystals in combination with therapeutically active agent(s) effective in the treatment of upper respiratory inflammation as well as those agents effective in the treatment of the underlying causes thereof, directly to, and uniformly upon the epithelial lining of the upper respiratory system. The lipid crystals and therapeutically active agent(s) are then deposited upon the epithelial tissue lining of the upper respiratory system whereupon the mixture forms an amorphous spread film effectively carrying said therapeutically active agent effective in the treatment of upper respiratory inflammation and/or the underlying cause thereof, uniformly therethrough and thereupon.
As stated in further detail below, the therapeutically active agent is advantageously selected to be effective in the treatment of upper respiratory inflammation as well as agents effective in the treatment of the underlying causes of said immune responses leading to the above-described inflammatory responses. For example, such agents may be selected to be effective in the treatment of viral or bacterial infections, (as well as combinations thereof) underlying and causative of said inflammatory reactions. Therefore, the second preferred method of the present invention provides a method of administering therapeutically active agents directly to the epithelial lining of the upper respiratory system wherein said therapeutically active agents provide effective treatment for the subject inflammatory condition such as, for example edemaxe2x80x94as well as the underlying causes thereofxe2x80x94while, simultaneously, the mixture of lipid crystals acts to directly and effectively open the air ways and air spaces by decreasing the surface tension of the viscous mucous exudate thereupon.
The lipid crystals deposited upon the air/liquid interface of said epithelial surfaces lining the upper respiratory system and the air/liquid interface resident thereupon is comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity and to serve as a carrier for selected therapeutic agent(s). In addition, the spreading agent deposited therewith provides complete and uniform distribution of the surfactant and therapeutic agent(s) throughout the lining of the upper respiratory system resulting in substantial decreases in air way resistance.
Administration of the lipid crystals through nasal or oral inhalation results in effective deposition of said crystals uniformly upon the epithelial mucosa of the entire upper respiratory system. Such deposition effectively decreases the surface tension of said surfaces. In those instances where, as discussed above, the increased surface tension and proximal airway swelling associated with upper respiratory inflammation and congestion has caused partial obstruction of the upper respiratory tract, the surface tension lowering properties of the lipid crystals acts to promote separation of proximal walls resulting in increased airway volume and a decrease to air flow resistance. In those embodiments of the present invention wherein delivery of therapeutically active agents to the upper respiratory system is provided, said agents are selected to be effective in the treatment of the disorder underlying and leading to an upper respiratory inflammation. It is contemplated that such disorders may be of a microbial, for example, a viral, protozoic, bacterial, fungal; or non-microbial, such as, for example, particulate or toxic/irritant chemical origin.
In some instances, more than one such agent may be carried by means of the lipid crystals to the upper respiratory mucosa. Such agents are contemplated to be antibiotics, antiviral agents, anti-inflammatory agents (steroid and non-steroid) anti-histamines and decongestants as well as combinations thereof.
The lipids utilized in practicing the method of the present invention may be advantageously selected to be phospholipids, neutral lipids or mixtures thereof. The phospholipids utilized may be further advantageously selected to be any phospholipid of the class known as phosphatidlycholine including any fully saturated diacyl phosphatidlycholine including 1,2 dipalmitoyl phosphatidylcholine (DPPC); a diacylphosphatidylglycerol; a diacylphosphatidylethanolamine; a diacylphosphatidylserine; a diacylphosphatidylinositol; sphingomyelin, Cardiolipin, lysophospholipid; a plasmalogen; a diether phosphonolipid; or a dialklyphospholipid.
The cholesteryl esters utilized in practicing the method of the present invention may be advantageously selected to be cholesteryl palmitate, cholesteryl oleate or cholesteryl stearate. Carbohydrates utilized in the present invention may be advantageously selected to be glucose, fructose, galactose, pneumogalactan, or dextrose. Proteins especially suited and advantageously selected for use in the present invention include albumin, pulmonary surfactant specific proteins A or B or C or D, their synthetic analogs, and mixtures thereof.
The fluorocarbon propellants may be advantageously selected to be chlorofluorocarbon propellants, hydrofluorocarbons or mixtures thereof. In addition, the present invention contemplates carbon dioxide as a suitable propellant. The mixture is advantageously prepared to yield crystalline forms that demonstrate a particle size equal to or less than 16 microns in diameter. The diminutive nature of the crystalline particles is, as discussed in detail below, highly advantageous in enabling dispersion and application of the aerosolized mixture.
The therapeutically active agent(s) referred to throughout this disclosure and in the claims refer to those agents, discussed in detail below that effectively reduce or eliminate the subject inflammatory effects as well as agents that treat the underlying precipitating factors thereof as discussed here-above and hereafter.
Throughout the specification and claims, the phrase xe2x80x9ctherapeutically active agentxe2x80x9d includes any substance which is capable of altering a biologic, physiologic and/or immunologic function, in nature or degree and includes those substances generally referred to as pharmacologic agents and drugs, including nucleic acids utilized in gene therapy, in order to provide treatment of the symptoms or underlying causes of the subject inflammation; the term xe2x80x9cfluorocarbonsxe2x80x9d includes the class of both chlorofluorocarbons and, hydrofluorocarbons; the term xe2x80x9clipidsxe2x80x9d includes the class of phospholipids including, but not limited to PC, PG, PE, PI and Cardiolipin; and the phrase xe2x80x9cspreading agent(s)xe2x80x9d refer to and includes PG, PE, PS, PI, Sph., Card., lysophospholipids, plasmalogens, dialkylphospholipids, and all others in the class phospholipid as well as cholesteryl esters (like CP), proteins and carbohydrates.
Throughout this specification and claims, the phrase xe2x80x9cspreading agent(s)xe2x80x9d refers to compounds, as listed above, which assist the one or more lipid such as, for example, DPPC, in rapidly adsorbing and forming an amorphous spread film on air/liquid interfaces such as that found upon the epithelial lined lumen of the auditory tube. In addition, the compounds referred to as xe2x80x9cspreading agent(s)xe2x80x9d, together with the one or more lipids, are responsible for achieving and maintaining biophysical properties including, but not limited to, reduction of intermolecular attractive forces, surface tension, and the resultant attractive forces generated thereby, that tend to cause opposed surfaces, such as the lateral and medial epithelial lined lumen walls of the auditory tube, to adhere to each other.
The major lipid component utilized in practicing a preferred embodiment of the present invention is advantageously selected to be phospholipid 1,2 dipalmitoyl, phosphatidlycholine (DPPC). DPPC is the most surface active of the phospholipids or any of the subclass of fully saturated acyl chain phospholipids. That is to say that DPPC, in combination with any spreading agent(s) disclosed herein, has a maximum effect in reducing surface tension at an air/liquid interface.
Another, minor lipid component that also acts as a spreading agent for the major component is advantageously selected to be diacylphosphatidylglycerol (PG). The number of carbon atoms in the acyl chains R and Rxe2x80x2, (see PG formula below) can vary between 8 and 22 and may or may not be fully saturated. DPPC and PG can be synthesized. However, since DPPC and PG are the main phospholipid constituents of cells, they are also readily extractable from such cells by non-polar solvents, i.e., chloroform, ether, acetone. DPPC""s structural formula is: 
Phospholipids such as DPPC and CP may be obtained commercially, in a highly purified form from Fluka Chemical Co. of Ronkonkoma, N.Y.; Sigma Chemical CO. of St. Louis Mo.; and Avanti Polar Lipids of Birmingham, Ala. and Primedica of Cambridge, Mass.
DPPC and PG are preferred component(s) advantageously utilized in the present inventions methods for administering therapeutically active agents to the middle ear and auditory tube. In addition, these lipids increase the pressure equalizing performance of the auditory tube by direct result of their surfactant qualities. DPPC may be selected to be present in the composition over a fairly wide range. Percentages of DPPC may be s as low as 70% and as high as 99.5% of the lipids by weight with little change in the in-vitro properties, and the effectiveness of the present method. However, 99.5% DPPC by weight is selected for the preferred embodiment.
Throughout this disclosure and within the claims, the terms xe2x80x9creducing resistance to air flow,xe2x80x9d reducing airway resistance,xe2x80x9d and xe2x80x9cimproving air flowxe2x80x9d singly, in combination and interchangeably all refer to the reduction of the force required to enable inspiratory and expiratory air through the air spaces and air ways of the upper respiratory system. The resistance referred to results from: reduction of the volume, partial obstruction, or complete occlusion of the upper respiratory airways and air spaces by swelling of the epithelium lining thereof; reduction of the volume, partial obstruction or complete obstruction of said air ways and air spaces by secretions resident upon said epithelial lining; and reduction of the volume, partial obstruction or complete obstruction of said air ways and air spaces by fluids collecting therewithin resulting from the effects of an immune response. In those embodiments of the present invention wherein the aerosolized mixture of lipid crystals does not include, or act as a carrier for, a therapeutically active agent(s), the above-described reduction in resistance to air flow is brought about by the separation of proximal upper respiratory epithelial surfaces by means of decreasing the surface tension thereupon. The term xe2x80x9cproximal upper respiratory epithelial surfacesxe2x80x9d as utilized throughout this specification and throughout the claims, refers to portions of the epithelial surface, lining the upper respiratory air ways and air spaces which, due to close proximity and/or opposition to each other, may come into contact as the result of, for example, epithelial or sub-epithelial edema, excess surface secretions, high surface tension, high negative air pressure or any combination thereof.
In those instances where the aerosolized mixture of lipid crystals does include and act as a carrier for a therapeutically active agent(s), the above-described reduction in resistance to air flow is brought about by: lowering the surface tension of proximal epithelial walls of and decreasing the pooling of secretions within said air ways and air spaces by means of said lipid crystals; and by reducing or temporarily halting the inflammatory response causing the edema, and excess viscous secretions by i. direct anti-inflammatory effect, ii by treating the triggering factor of said inflammation, or iii. by combinations thereof.
For example, in those instances of the present invention wherein an anti-histamine is the therapeutically active agent, proximal walls of epithelial mucosa lined air ways of the upper respiratory system that are adherent to each other are separated and opened by means of both lipid crystal mediated reduction of surface tension and, upon action of said anti-histamine, reduction of edema, reduction of mucous volume, and decrease in the viscous nature thereof.
Another lipid that can be utilized in practicing the methods of the present invention is cholesteryl palmitate( CP), which also serves as a spreading agent. This cholesteryl ester is a neutral lipid which belongs to a class of organic compounds that are also cell constituents and are extractable by non-polar solvents such as chloroform, methanol, ether, etc. The structural formula of CP is: 
CP may be obtained commercially in a highly purified form from Fluka Chemical Co. and Sigma Chemical Co and Primedica. The CP component constitutes a minor portion of the composition, since it is selected to be present in an amount ranging from 0.5% to 10% by weight. Also, the preferred ratio of DPPC to CP is 99.5 DPPC to 0.5 CP by weight. However, the percentages may be altered within that range without undue interference in desired properties needed for drug delivery and surfactant activity.
The term xe2x80x9ctherapeutically active agents effective in the treatment of upper respiratory inflammationxe2x80x9d as utilized in and throughout this specification and claims, refers to those drugs effective in direct treatment of the inflammatory response causing the above-described air way and air space resistance as well as those drugs effective in the treatment of the underlying or precipitating cause of such inflammation such as, for example: treatment of infection, of microbial origin, such as, for example, viral, protozoic, bacterial, fungal and/or parasitic origin-; treatment of non-microbial allergic response resulting from antigenic matter such as, for instance, particulate (e.g. pollens and dust) and chemical triggers; as well as treatment of autoimmune disease causative of such inflammation. Therefore, it is contemplated that embodiments of the present invention may include as a therapeutic agent, singly or in combination: drugs effective in the direct treatment of the subject inflammation such as, for example, corticosteroids including, for example, betamethasone, including, for example, betamethasone dipropionate and betamethasone valerate as well as all other effective formulations; de-congestive agents such as phenylephrine, including, for example, phenylephrine HCL and phenylephrine bitartrate and all other effective formulations thereof; anti-viral agents such as, for example zovirax; and antibiotics including, for example erythromycin, amoxicillin, zythromax, and augmentin (amoxicillin and clavuliic acid) in all of their effective formulations. The term xe2x80x9call of their effective formulationsxe2x80x9d as used throughout this specification and in the claims refers to those specific species of a particular therapeutic agent effective in the treatment of the above-described upper respiratory do. It is also contemplated that said therapeutically effective agents include nucleic acids as well as the vectors thereof as utilized in gene therapy.
The combination of lipid component(s) and spreading agent component(s) disclosed herein, may be referred to, collectively, as the xe2x80x9ccarrierxe2x80x9d when said combination is mixed with a therapeutically active agent so as to act as a carrier therefore. When practicing the method of the present invention wherein therapeutically active agents are administered directly to the epithelial lining of the upper respiratory system, it is preferred that carrier, the mixture of one or more lipids and one or more spreading agents, be comprised of a mixture of DPPC and CP in a 200:1 ratio (by weight). However, it has been found that a ratio range of from 5:1 to 300:1 (DPPC/CP) will also produce an effective carrier for this embodiment. If, for example, the therapeutic agent is selected to be betamethasone, the weight ratio of betamethasone to carrier (DPPC/CP) is advantageously selected to be 1 microgram betamethasone to 5 milligrams carrier. However, it has been found that a weight ratio range of 0.5 to 1000 micrograms betamethasone/5 milligrams carrier yields an effective and functional mixture.
When practicing the method of the present invention wherein the therapeutically active agent is selected to be phenylephrine it is preferred to select the weight ratio of phenylephrine to carrier to be 160 micrograms/995 milligrams. However, it has also been found that a weight ratio range of from 50 to 5000 micrograms (phenylephrine): 995 to 900 milligrams carrier, respectively, forms an effective mixture and functional mixture. The term xe2x80x9ceffective and functional mixturexe2x80x9d as utilized throughout this application and in the claims refers to the effectiveness of the mixture of lipid crystals in combination with said therapeutically active agent resulting from the combinations disclosed herein in: (a) reaching the target tissue of the epithelium of the upper respiratory system; (b) reducing the surface tension thereupon; and (c) delivering a uniform dose of therapeutic agent directly to and spreading uniformly upon and throughout the epithelium lining the upper respiratory tract so as to effectively bring symptomatic relief and/or resolution of the afore-mentioned pathological conditions underlying upper respiratory inflammation as well as acting, by means of said lipid crystals to open the air ways and air spaces by reduction of surface tension and elimination of pooled fluids.
When practicing the method of the present invention wherein the therapeutically active agent is selected to be the antibiotic erythromycin, the ratio of erythromycin to carrier is advantageously selected to be 200 mg antibiotic to 800 mg carrier (DPPC/CP) by weight. However, a weight range of from 50 to 200 mg erythromycin: from 950 to 800 mg carrier, respectively, has been found to be fully effective in practicing the present method.
The fluorocarbon propellants utilized in practicing the method of the present invention, namely: trichlorodifluoromethane, dichlorodifluoromethane, and tetrafluoromethane or mixtures thereof, which are commercially available from Union Carbide Corp., Danbury, Conn. and Armstrong Laboratories, West Roxbury Mass. are advantageously selected for formation of the lipid crystalline figures of the present invention. The fluorocarbon propellants are present over a range of 2 to 30 times the amount, by weight, of lipid, but components of lipid and fluorocarbon propellants both are needed in order to obtain the required lipid crystalline figures.
In practicing the methods of the present invention wherein therapeutically effective agents are administered directly to the epithelial tissue lining the upper respiratory tract, DPPC is advantageously selected as the major lipid component since the amphoteric nature of this phospholipid allows the molecule to act as a carrier for any drug or therapeutic agent. However, the presence of a charge on other lipid components (a negative charge on PG, for example) would alter and further improve the carrying capacity of the lipid crystals for a particular therapeutic agent.
In addition to erythromycin and amoxicillin, the method of the present invention also contemplates selecting zythromax and Augmentin (amoxicillin+clavulinic acid) as antibiotic therapeutic agents and zovirax as an anti-viral agent. However, because of the highly amphoteric nature of the carrier utilized herein, the use of any presently known and available, as well as anti-viral, antibiotic or gene therapy developed in the future capable of providing effective treatment of infections of the upper respiratory tract are contemplated and fully functional with the methods and compositions herein.